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药物详细合成路线

Name Mivobulin isethionate;NSC-635370 [(1:1) salt];NSC-370147(racemic hydrate);NSC-350386(racemic HCl hydrate);NSC-613863 [(+)-(R)-isomer];CI-980;NSC-613862(free base)
Chemical Name (-)-(S)-N-(5-Amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamic acid ethyl ester 2-hydroxyethylsulfonate
CAS 126268-81-3
Related CAS 122332-18-7 (free base)
Formula C19H25N5O6S
Structure
Formula Weight 451.505
Stage I/II 期临床
Company Pfizer (Originator), National Cancer Institute (Codevelopment)
Activity/Mechanism Brain Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Oncolytic Drugs, Antimitotic Drugs, Microtubule-Stabilizing Agents
Syn. Route 3
Route 1
synthesis of ci-980:the condensation of n-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (i) with (1r,2s)-2-amino-1-phenyl-1-propanol (ii) by means of triethylamine in refluxing ethanol gives (1s,2r)-n-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (iii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (iv). the reductocyclization of (iv) with h2 over rani in glacial acetic acid affords the free base of title compound (v), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate (i)
1-azabicyclo[3.2.1]octan-6-one (ii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate (iii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate (iv)
2-(1-azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt (v)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    carroll, t.g. jr. (southern research institute); (2s)-(5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid, ethyl ester. ep 0336345; jp 1989305087; us 4866059 .

Route 2
synthesis of [14c]-labeled ci-980:the reaction of n-(ethoxycarbonyl)-l-alanine (vii) with n-methoxy-n-methylamine (viii) by means of carbonyldiimidazole (cdi) in thf/dichloromethane gives the corresponding amide (ix), which is treated with phenylmagnesium bromide (1 mol) yielding the bromomagnesium salt (x). the bromination of [14c]-labeled benzene (xi) with br2/hbr/h2o2 gives the labeled bromobenzene (xii), which is converted into the corresponding grignard reagent (xiii) by reaction with mg and dibromoethane in ether. the reaction of the previously obtained magnesium salt of alaninamide (x) with the labeled grignard reagent (xiii) affords the labeled carbamate (xiv), which is reduced with nabh4 in methanol and treated with koh giving a mixture of the oxazolidinone (xv) and the aminoalcohol (xvi), separated by acidic extraction. the hydrolysis of the oxazolidinone (xv) with koh yielded the desired aminoalcohol (xvi). the aminoalcohol (xvi) by means of triethylamine in refluxing ethanol gives (1s,2r)-n-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (xvii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (xviii). the reductocyclization of (xviii) with h2 over rani in glacial acetic acid affords the free base of title compound (xix), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
1-azabicyclo[3.2.1]octan-6-one (xvi)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate (xvii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate (xviii)
2-(1-azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt (ix)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
(5r,6r)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vii)
ethyl 2-anilinoacetate (viii)
ethyl 2-(1-phenylhydrazino)acetate (ix)
ethyl 2-[(1s,2s,13s,21r)-22-(cyclopropylmethyl)-2,16-dihydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (x)
ethyl 2-[(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (xi)
(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-hydroxyethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol (xii)
(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol (xiv)
(1s,2r)-n,n-diethyl-2-formyl-1-phenylcyclopropanecarboxamide (xv)
2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone (xiii)
5-bromo-2,2-difluoro-1,3-benzodioxole (xi)
(xii)
(xiii)
(xiv)
(xv)
(4as,6r,7r,8s,8as)-6-({(2r,3s,4r,5r,6s)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2h-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl benzoate (xvi)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    woo, p.w.k.; lee, h.t.; synthesis of [14c]ci-980, ethyl [5-amino-1,2-dihydro-2(s)-methyl-3-[14c]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. j label compd radiopharm 1994, 34, 1, 1-10.

Route 3
3) synthesis of [3h]-labeled ci-980:the reaction of butyllithium with m-dibromobenene (xvii) in ether gives the monolithium derivative (xviii), which is condensed with n-(ethoxycarbonyl)-l-alanine (vii) yielding the carbamate (xix). the reduction of (xix) with nabh4 in methanol affords the hydroxylated carbamate (xx), which is treated with naoh in methanol to give the aminoalcohol (xxi). the condensation of n-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (i) with 2(s)-amino-1-(3-bromophenyl)-1-propanol (xxi) by means of triethylamine in refluxing ethanol gives n-[2-amino-4-[2-(3-bromophenyl)-2-hydroxy-1(s)-methylethylamino]-3-nitropyridin-6-yl]carbamic acid ethyl ester (xxii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (xxiii). the reductocyclization of (xxiii) with fe and acetic acid affords the 3-bromo analogue of ci-980 (xxiv), which is finally hydrogenated with 3h2 over pd/c in thf, and treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate (i)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
(5r,6r)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vii)
(1s,2r)-n,n-diethyl-2-[(1r)-1-hydroxy-3-(trimethylsilyl)-2-propynyl]-1-phenylcyclopropanecarboxamide (xvii)
(1s,2r)-2-[(1r)-1-azido-3-(trimethylsilyl)-2-propynyl]-n,n-diethyl-1-phenylcyclopropanecarboxamide (xviii)
(4s)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one (xix)
octanal (xx)
(4s)-4-benzyl-3-[(2s,3r)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one (xxi)
(4s)-4-benzyl-3-((2s,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one (xxii)
(2s,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid (xxiii)
2,4,6-trichlorobenzoyl chloride (xxiv)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    lee, h.t.; woo, p.w.k.; synthesis of [3h]ci-980, ethyl[5-amino-1,2-dihydro-2(s)-methyl-3(3-[3h]phenyl)pyrido[3,4-b] pyrazin-7-yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. j label compd radiopharm 1994, 34, 1, 11-16.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名(-)-(S)-N-(5-氨基-2-甲基-3-苯基-l,2-二氢吡啶并[3,4-b]吡嗪-7-基)氨;英文名Mivobulin isethionate;NSC-635370 [(1:1) salt];NSC-370147(racemic hydrate);NSC-350386(racemic HCl hydrate);NSC-613863 [(+)-(R)-isomer];CI-980;NSC-613862(free base);CAS[126268-81-3]

 
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